The invention relates to a device for a substantially simultaneous synthesis of a plurality of samples that are particularly for use in the automated laboratory work in the field of the combinatorial chemistry.
Sample particles, (“beads” or “Perlen”), have been used in separations and synthesis in the laboratory technical field for tenth of years. These particles mostly are glass or polymeric globules that have diameters of 0.01 mm up to 1 mm, typically about 0.1 mm, which are filled, dry or pre-swelled, as a loose material into a receptacle where they are then flushed by a liquid, whereby an adsorption process or a reaction process takes place between the solid phase surface of the particles and the liquid surrounding the particles. Methods of the column chromatography (for example, gel filtration), of the column extraction, of the immundiagnosis, of the bio-molecule purification (for example, DNA cleaning), as well as of the homogeneous and heterogeneous synthesis (of oligonucleotides, peptides or combinatorial substance libraries) utilize these techniques. In addition to the automation and miniaturizing of laboratory techniques, the parallelizing of the same is of great interest in obtaining a higher sample throughput and, hence, to speed up otherwise time-consuming procedures. To this end, samples are very often arranged in a raster so that the identity (origin, quality) of the sample can be associated to an area coordinate. Such coordinates are very easily to be detected in particular in automated systems of sample handling.
Therefore, so-called micro-titer plates have been developed for liquid samples, which support cavities in right-angular arrangements of 8·12 (96 samples) 16-24 (384) or 32·48 (1536). Thereby, the dimensions of the cavities of these sample holders depend on such volumes that can be reliably dosed by the commercially available devices (pipettes), and follow a miniaturizing continuously progressing with the dosing technology, what is simplified by the capability of an ali-quote (distribution of a mother-sample into different daughter-samples) of liquids at will.
Within the frame of work for miniaturizing laboratory procedures there is searched for possibilities to distribute sample particles, in analogy to the arrangement of liquid samples, in a two-dimensional raster. Since the miniaturizing of dosing liquids has already advanced very far, so the single particle becomes the smallest unit. Furthermore, there is the demand to handle high quantities, as it is common use when working with particles. 1-g polymer resin contains about 1 million particles.
There are different solutions known for filling micro-titer plates or reaction vessels.
So WO 98/24543 A1 describes a device for transferring liquids in which, inter alia, a micro-titer plate is provided, the chambers of which have at least one opening in their bottom area that is dimensioned in a way that, in the course of a filling operation, the passage of the liquid through this opening due to capillary forces is avoided. In WO 98/06490 A1 a device for an organic solid phase synthesis is described, in which the reaction vessel is arranged above a collective vessel for receiving liquids in such a way that the transfer of the liquid can be attained by generating a low pressure, whereas the liquid is held in the reaction vessel by a slight overpressure. From WO 97/19749 A1 there is a device for addressable combinatorial substance libraries known, in which one substance each is represented in a capillary tube, whereby the filling with liquids is obtained by capillary forces. In WO 97/37755 A1 a plate is described that contains a plurality of reaction cells being arranged in rows and columns, which are supplied with liquids by pumps. Furthermore, the specifications WO 97/43629 A1 and WO 98/16315 A1 describe distribution systems for liquids, which are comprised of a plurality of plates, whereby the liquid flow is operated and controlled by a capillary barrier and by electro-kinetic pumps, respectively.
The miniaturizing of the support plates mentioned goes along with the miniaturizing of the corresponding filling technologies and meets its critical geometric or time limits when conventional automated pipetting devices are used, since each single sample particle has to be supplied with liquids.